The long-term objectives of this proposal are to advance our knowledge of the physiological effects of marijuana abuse and to elucidate the neuroendocrine function of the endogenous cannabinoid system. This proposal will focus on the effects of cannabinoids on the hypothalamic-pituitary-adrenal (HPA) axis, a system which plays a critical role in coordinating the neuroendocrine response to stress. The specific aims of this proposal address the ability of cannabinoids to stimulate adrenocorticotropin hormone (ACTH) and corticosteroid release in the female and understanding the role of corticotropin-releasing hormone (CRH) in this response. Furthermore, the role of CRH in the ability of cannabinoids to decrease luteinizing hormone (LH) and induce catalepsy and alterations in feeding behavior will be investigated. Moreover, the site and mechanisms by which cannabinoids elicit their effects on CRH release and the modulation of the CNS responsiveness to cannabinoids by corticosteroids will be investigated. Initially, the role of cannabinoid receptors in the ability of marijuana to alter hormone secretion and feeding behavior will be determined by examining the effects of specific cannabinoid receptor agonists (levonantradol,methanandamide) and antagonists (SR141716A) on ACTH, corticosteroid and LH secretion and feeding behaviors in OVX rats. Secondly, the role of CRH in the ability of THC to alter hormone release, feeding behavior and catalepsy will be determined by measuring hypothalamic CRH gene expression following acute treatment with cannabinoid receptor agonists. The role of CRH as mediator of cannabinoid effects will also be determined utilizing a CRH receptor antagonist (D-PheCRH12-41) and studying its ability to block cannabinoid action. Thirdly, the site and mechanism of cannabinoid action in the stimulation of the HPA axis will be determined by addressing the role of serotonin in the ability of cannabinoids to affect the HPA axis and by examining the hypothalamus, hippocampus, amygdala, raphe nuclei) as potential sites of cannabinoid action. Lastly, the ability of glucocorticoids to modulate cannabinoid actions on the HPA axis will be investigated. Our findings using female rats will not only address the potential neuroendocrine role of endogenous cannabinoids, but will provide new information on how cannabinoids modulate the HPA system; activation of which may have significant consequences on the endocrine, reproductive and immune systems of the human marijuana user.